Stability and pharmacokinetics of separase inhibitor-Sepin-1 in Sprague-Dawley rats

Biochem Pharmacol. 2020 Apr:174:113808. doi: 10.1016/j.bcp.2020.113808. Epub 2020 Jan 10.

Abstract

Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide) is a potent separase inhibitor that impedes cancer cell growth, cell migration, and wound healing, suggesting that Sepin-1 possesses a great potential to target separase-overexpressing tumors. As a part of the IND-enabling studies to bring Sepin-1 to clinic, herein we report the results from a 28-day repeat-dose pharmacokinetic study of Sepin-1 in rats. Sepin-1 was intravenously administered to Sprague-Dawley rats once daily for 28 days at three different (5, 10, and 20 mg/kg) doses. Blood samples were collected after administration of doses on days 1 and 28. Sepin-1 is unstable and isomerizes in basic solutions, but it is stable in acidic buffer such as citrate-buffered saline (pH 4.0). UHPLC-MS analysis indicated Sepin-1 was rapidly metabolized in vivo. One of the major metabolites was an amine adduct of 2,2-dimethyl-5-nitro-2H-benzimidazole (named Sepin-1.55). The concentration of Sepin-1.55 in blood samples was Sepin-1 dose-dependent and used for pharmacokinetic analysis of Sepin-1. Tmax was approximately 5-15 min. The data suggest that no Sepin-1 accumulation occurred from daily repeat dosing and similar exposures on the first and final day of dosing. Data also suggest a gender difference, namely that female rats have more exposure and slower clearance than male rats. The data support that Sepin-1 is a potential drug candidate that can be further developed to treat Separase-overexpressing human tumors.

Keywords: Metabolite; Pharmacokinetics; Rats; Separase inhibitor; Sepin-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzimidazoles* / chemistry
  • Benzimidazoles* / pharmacokinetics
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cysteine Proteinase Inhibitors* / chemistry
  • Cysteine Proteinase Inhibitors* / pharmacokinetics
  • Drug Stability
  • Female
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Separase / antagonists & inhibitors*
  • Separase / blood

Substances

  • Benzimidazoles
  • Cysteine Proteinase Inhibitors
  • sepin-1
  • Separase